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nmdar inhibition

J Xu, B J Hartley, P Kurup, A Phillips, A Topol, M Xu, C Ononenyi, E Foscue, S-M Ho, T D Baguley, N Carty, C S Barros, U Müller, S Gupta, P Gochman, J Rapoport, J A Ellman, C Pittenger, B Aronow, A C Nairn, M W Nestor, P J Lombroso, K J Brennand
The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein tyrosine Phosphatase) is an important regulator of synaptic function. STEP normally opposes synaptic strengthening by increasing N-methyl D-aspartate glutamate receptor (NMDAR) internalization through dephosphorylation of GluN2B and inactivation of the kinases extracellular signal-regulated kinase 1/2 and Fyn. Here we show that STEP61 is elevated in the cortex in the Nrg1(+/-) knockout mouse model of schizophrenia (SZ). Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDARs from synaptic membranes and reverses behavioral deficits in Nrg1(+/-) mice...
October 18, 2016: Molecular Psychiatry
Meilin Tian, Shixin Ye
Allostery is essential to neuronal receptor function, but its transient nature poses a challenge for characterization. The N-terminal domains (NTDs) distinct from ligand binding domains are a major locus for allosteric regulation of NMDA receptors (NMDARs), where different modulatory binding sites have been observed. The inhibitor ifenprodil, and related phenylethanoamine compounds specifically targeting GluN1/GluN2B NMDARs have neuroprotective activity. However, whether they use differential structural pathways than the endogenous inhibitor Zn(2+) for regulation is unknown...
October 7, 2016: Scientific Reports
Rong Hu, Juan Chen, Brendan Lujan, Ruixue Lei, Mi Zhang, Zefen Wang, Mingxia Liao, Zhiqiang Li, Yu Wan, Fang Liu, Hua Feng, Qi Wan
Ionotropic activation of NMDA receptors (NMDARs) requires agonist glutamate and co-agonist glycine. Here we show that glycine enhances the activation of cell survival-promoting kinase Akt in cultured cortical neurons in which both the channel activity of NMDARs and the glycine receptors are pre-inhibited. The effect of glycine is reduced by shRNA-mediated knockdown of GluN2A subunit-containing NMDARs (GluN2ARs), suggesting that a non-ionotropic activity of GluN2ARs mediates glycine-induced Akt activation. In support of this finding, glycine enhances Akt activation in HEK293 cells over-expressing GluN2ARs...
October 3, 2016: Scientific Reports
Ana B Sanchez, Kathryn E Medders, Ricky Maung, Paloma Sánchez-Pavón, Daniel Ojeda-Juárez, Marcus Kaul
BACKGROUND: The chemokine receptor CXCR4 (CD184) and its natural ligand CXCL12 contribute to many physiological processes, including decisions about cell death and survival in the central nervous system. In addition, CXCR4 is a co-receptor for human immunodeficiency virus (HIV)-1 and mediates the neurotoxicity of the viral envelope protein gp120. However, we previously observed that CXCL12 also causes toxicity in cerebrocortical neurons but the cellular mechanism remained incompletely defined...
2016: Journal of Neuroinflammation
Zhong Wang, Yibin Wang, Xiaodi Tian, Haitao Shen, Yang Dou, Haiying Li, Gang Chen
Transient receptor potential channel 1/4 (TRPC1/4) are considered to be related to subarachnoid hemorrhage (SAH)-induced cerebral vasospasm. In this study, a SAH rat model was employed to study the roles of TRPC1/4 in the early brain injury (EBI) after SAH. Primary cultured hippocampal neurons were exposed to oxyhemoglobin to mimic SAH in vitro. The protein levels of TRPC1/4 increased and peaked at 5 days after SAH in rats. Inhibition of TRPC1/4 by SKF96365 aggravated SAH-induced EBI, such as cortical cell death (by TUNEL staining) and degenerating (by FJB staining)...
2016: Scientific Reports
Johan-Till Pougnet, Benjamin Compans, Audrey Martinez, Daniel Choquet, Eric Hosy, Eric Boué-Grabot
Plasticity at excitatory synapses can be induced either by synaptic release of glutamate or the release of gliotransmitters such as ATP. Recently, we showed that postsynaptic P2X2 receptors activated by ATP released from astrocytes downregulate synaptic AMPAR, providing a novel mechanism by which glial cells modulate synaptic activity. ATP- and lNMDA-induced depression in the CA1 region of the hippocampus are additive, suggesting distinct molecular pathways. AMPARs are homo-or hetero-tetramers composed of GluA1-A4...
2016: Scientific Reports
Roopashri Holehonnur, Aarron J Phensy, Lily J Kim, Milica Milivojevic, Dat Vuong, Delvin K Daison, Saira Alex, Michael Tiner, Lauren E Jones, Sven Kroener, Jonathan E Ploski
UNLABELLED: Reconsolidation updating is a form of memory modification in which an existing memory can become destabilized upon retrieval and subsequently be modified via protein-synthesis-dependent reconsolidation. However, not all memories appear to destabilize upon retrieval and thus are not modifiable via reconsolidation updating approaches and the neurobiological basis for this remains poorly understood. Here, we report that auditory fear memories created with 10 tone-shock pairings are resistant to retrieval-dependent memory destabilization and are associated with an increase in the synaptic GluN2A/GluN2B ratio in neurons of the basal and lateral amygdala (BLA) compared with weaker fear memories created via one or three tone-shock pairings...
September 7, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Mariana P C Ribeiro, José B A Custódio, Armanda E Santos
Glutamate has a trophic function in the development of the central nervous system, regulating the proliferation and migration of neuronal progenitors. The resemblance between neuronal embryonic and tumor cells has paved the way for the investigation of the effects of glutamate on tumor cells. Indeed, tumor cells derived from neuronal tissue express ionotropic glutamate receptor (iGluRs) subunits and iGluR antagonists decrease cell proliferation. Likewise, iGluRs subunits are expressed in several peripheral cancer cells and blockade of the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) ionotropic glutamate receptor subtypes decreases their proliferation and migration...
September 1, 2016: Cancer Chemotherapy and Pharmacology
Raeesah Maqsood, Trevor W Stone
Gastro-intestinal (GI) microbiota and the 'gut-brain axis' are proving to be increasingly relevant to early brain development and the emergence of psychiatric disorders. This review focuses on the influence of the GI tract on Brain-Derived Neurotrophic Factor (BDNF) and its relationship with receptors for N-methyl-D-aspartate (NMDAR), as these are believed to be involved in synaptic plasticity and cognitive function. NMDAR may be associated with the development of schizophrenia and a range of other psychopathologies including neurodegenerative disorders, depression and dementias...
August 23, 2016: Neurochemical Research
Nadezhda V Povysheva, Jon W Johnson
Memantine is one of the few drugs currently approved for treatment of Alzheimer's disease (AD). The clinical effects of memantine are thought to be associated with inhibition of NMDA receptors (NMDARs). Surprisingly, other open-channel NMDAR blockers have unacceptable side effects that prevent their consideration for AD treatment. One of the mechanisms proposed to explain the therapeutic benefits of memantine involves preferential decrease of excitatory drive to inhibitory neurons in the cortical circuitry and consequent changes in balance between excitation and inhibition (E/I)...
August 18, 2016: Neurobiology of Disease
Wei Liu, Zhaofa Xu, Tianyao Yang, Bin Xu, Yu Deng, Shu Feng
Methylmercury (MeHg) is an extremely dangerous environmental pollutant that induces severe toxic effects in the central nervous system. Neuronal damage plays critical roles mediating MeHg-induced loss of brain function and neurotoxicity. The molecular mechanisms of MeHg neurotoxicity are incompletely understood. The objective of the study is to explore mechanisms that contribute to MeHg-induced neurocyte injuries focusing on neuronal Ca(2+) dyshomeostasis and alteration of N-methyl-D-aspartate receptors (NMDARs) expression, as well as oxidative stress in primary cultured cortical neurons...
August 18, 2016: Molecular Neurobiology
Grace France, Diego Fernández-Fernández, Erica S Burnell, Mark W Irvine, Daniel T Monaghan, David E Jane, Zuner A Bortolotto, Graham L Collingridge, Arturas Volianskis
In the CA1 area of the hippocampus N-methyl-d-aspartate receptors (NMDARs) mediate the induction of long-term depression (LTD), short-term potentiation (STP) and long-term potentiation (LTP). All of these forms of synaptic plasticity can be readily studied in the juvenile hippocampal slices but the involvement of particular NMDAR-subunits in the induction of these different forms of synaptic plasticity is currently unclear. Here, using NVP-AAM077, Ro 25-6981 and UBP145 to target GluN2A-, 2B- and 2D-containing NMDARs respectively, we show that GluN2B-containing NMDARs (GluN2B) are involved in the induction of LTD, STP and LTP in slices prepared from P14 rat hippocampus...
August 11, 2016: Neuropharmacology
Alex Savchenko, Gary B Braun, Elena Molokanova
Glutamatergic cytotoxicity mediated by overactivation of N-methyl-d-aspartate receptors (NMDARs) is implicated in numerous neurological disorders. To be therapeutically viable, NMDAR antagonists must preserve physiological role of synaptic NMDARs (sNMDARs) in synaptic transmission and block only excessive pathological activation of NMDARs. Here we present a novel NMDAR antagonist that satisfies this two-fold requirement by exploiting spatial differences in NMDAR subcellular locations. Specifically, we designed a hybrid nanodrug (AuM) to be larger than the synaptic cleft by attaching memantine, NMDAR antagonist, via polymer linkers to a gold nanoparticle...
September 14, 2016: Nano Letters
Zhengchang Liao, Xiaocheng Zhou, Ziqiang Luo, Huiyi Huo, Mingjie Wang, Xiaohe Yu, Chuanding Cao, Ying Ding, Zeng Xiong, Shaojie Yue
Background. Intrauterine hypoxia is a common cause of fetal growth and lung development restriction. Although N-methyl-D-aspartate receptors (NMDARs) are distributed in the postnatal lung and play a role in lung injury, little is known about NMDAR's expression and role in fetal lung development. Methods. Real-time PCR and western blotting analysis were performed to detect NMDARs between embryonic days (E) 15.5 and E21.5 in fetal rat lungs. NMDAR antagonist MK-801's influence on intrauterine hypoxia-induced retardation of fetal lung development was tested in vivo, and NMDA's direct effect on fetal lung development was observed using fetal lung organ culture in vitro...
2016: BioMed Research International
Valentina Vengeliene, Nazzareno Cannella, Tatiane Takahashi, Rainer Spanagel
RATIONALE: The glutamatergic system plays a key role in the maintenance of drug use and development of drug-related conditioned behaviours. In particular, hyper-glutamatergic activity and N-methyl-D-aspartate receptor (NMDAR) activation may drive drug craving and relapse. Inhibition of kynurenine-3-monooxygenase (KMO) shifts the metabolic kynurenine pathway towards production of kynurenic acid, which leads to a reduction of glutamatergic/NMDAR activity via different mechanisms. OBJECTIVES: In this study, we investigated whether drug-seeking and relapse behaviour could be modified by the metabolic shift of endogenous kynurenine pathway...
September 2016: Psychopharmacology
G Smilin Bell Aseervatham, U Suryakala, Doulethunisha, S Sundaram, P Chandra Bose, T Sivasudha
The present study was aimed to evaluate the effect of apigenin 8-C-glucoside (Vitexin) and chlorogenic acid on epileptic mice induced by pilocarpine and explored its possible mechanisms. Intraperitonial administration of pilocarpine (85mg/kg) induced seizure in mice was assessed by behavior observations, which is significantly (p>0.05) reduced by apigenin 8-C-glucoside (AP8CG) (10mg/kg) and chlorogenic acid (CA) (5mg/kg), similar to diazepam. Seizure was accompanied by an imbalance in the levels of Gamma-aminobutyric acid (GABA) and glutamate in the pilocarpine administered group...
August 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Dana O Kravchick, Anna Karpova, Matous Hrdinka, Jeffrey Lopez-Rojas, Sanda Iacobas, Abigail U Carbonell, Dumitru A Iacobas, Michael R Kreutz, Bryen A Jordan
Elevated c-Jun levels result in apoptosis and are evident in neurodegenerative disorders such as Alzheimer's disease and dementia and after global cerebral insults including stroke and epilepsy. NMDA receptor (NMDAR) antagonists block c-Jun upregulation and prevent neuronal cell death following excitotoxic insults. However, the molecular mechanisms regulating c-Jun abundance in neurons are poorly understood. Here, we show that the synaptic component Proline rich 7 (PRR7) accumulates in the nucleus of hippocampal neurons following NMDAR activity...
September 1, 2016: EMBO Journal
Jing-Dun Xie, Shao-Rui Chen, Hong Chen, Wei-An Zeng, Hui-Lin Pan
Painful peripheral neuropathy is a severe adverse effect of chemotherapeutic drugs such as paclitaxel (Taxol). The glutamate N-methyl-d-aspartate receptors (NMDARs) are critically involved in the synaptic plasticity associated with neuropathic pain. However, paclitaxel treatment does not alter the postsynaptic NMDAR activity of spinal dorsal horn neurons. In this study, we determined whether paclitaxel affects presynaptic NMDAR activity by recording excitatory postsynaptic currents (EPSCs) of dorsal horn neurons in spinal cord slices...
September 9, 2016: Journal of Biological Chemistry
Beatrice M Pigott, John Garthwaite
Nitric oxide (NO) has long been implicated in the generation of long-term potentiation (LTP) and other types of synaptic plasticity, a role for which the intimate coupling between NMDA receptors (NMDARs) and the neuronal isoform of NO synthase (nNOS) is likely to be instrumental in many instances. While several types of synaptic plasticity depend on NMDARs, others do not, an example of which is LTP triggered by opening of L-type voltage-gated Ca(2+) channels (L-VGCCs) in postsynaptic neurons. In CA3-CA1 synapses in the hippocampus, NMDAR-dependent LTP (LTPNMDAR) appears to be primarily expressed postsynaptically whereas L-VGCC-dependent LTP (LTPL-VGCC), which often coexists with LTPNMDAR, appears mainly to reflect enhanced presynaptic transmitter release...
2016: Frontiers in Synaptic Neuroscience
Daping Xu, Haiyun Chen, Shinghung Mak, Shengquan Hu, Karl W K Tsim, Yuanjia Hu, Yewei Sun, Gaoxiao Zhang, Yuqiang Wang, Zaijun Zhang, Yifan Han
Alzheimer's disease is a progressive neurodegenerative disorder, characterized by irreversible impairment of memory and cognitive function. The exact causes of Alzheimer's disease still remain unclear and current single target drugs could only offer limited therapeutic effect to the patients. We have previously reported that T-006, a promising anti-Alzheimer's compound derived from Chinese medicinal component tetramethylpyrazine, might protect neurons through inhibiting the overproduction of intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS)...
October 2016: Neurochemistry International
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